The pathological hallmarks of Alzheimer's disease (AD) are extracellular amyloid ? (A?) deposits in the brain parenchyma and cerebral blood vessels (cerebral amyloid angiopathy, CAA) and intra-neuronal neurofibrillary tangles. CAA reflects an age-related failure of elimination of A? from the brain and is identified in 75-98% of AD patients. A? deposits in CAA affect cerebral blood flow, alter blood-brain barrier (BBB) permeability, interfere with A? clearance/efflux from the brain and trigger a cascade of inflammatory responses, leading to hemorrhages and dementia. According to the vascular hypothesis of AD, cerebral vascular damages initiate A? accumulation in the brain, resulting in dementia of AD. Thus, elucidation of the molecular pathogenesis of CAA is of paramount importance to identify therapeutic and preventive targets for AD. Although interleukin-17A (IL-17A) is generally thought to be a pro-inflammatory cytokine involved in autoimmune diseases, increasing lines of evidence support neuroprotective and beneficial effects of IL-17A. We have recently discovered that IL- 17A overexpression in the brain of an AD mouse model improves brain glucose metabolism and induces an approximately 4-fold decrease (1/4) in A? deposits/levels in the CAA, cerebrospinal fluid (CSF) and buffer soluble brain fraction, compared with their control animals. We also found that IL-17A upregulates certain ATP- binding cassette (ABC) transporters by activating ERK1/2 signaling in the brain endothelial cell culture. Such ABC transporters have been shown to enhance A? clearance from the brain and/or decrease brain A? levels in AD mouse models. Indeed, loss-of-function mutations in the genes of the ABC transporters are linked to high risk of AD and cerebrovascular disease. Moreover, defects in brain glucose metabolism are associated with AD and BBB dysfunction. Therefore, we hypothesize that IL-17A receptor (IL-17RA) signaling regulates expression of A?/ABC efflux transporters and glucose transporters in endothelial cells at the BBB and that deficiency of IL-17RA signaling increases A? levels in CAA and brain parenchyma and deteriorates glucose metabolism, leading to cognitive deficits in AD mouse models. To test the hypothesis, we will create AD mouse models with vascular endothelial cell-specific IL-17RA deficiency (eIL-17RA-/-). Using eIL-17RA-/- AD mouse models, we will determine expression levels of A?/ABC transporters, glucose transporters and tight junction proteins in brain vascular endothelial cells, and evaluate the effects of eIL-17RA-/- on AD-like pathophysiology and behavioral/cognitive functions. The immediate goal is to determine the role of endothelial IL-17RA signaling in AD pathogenesis. The long-term goals are to identify the molecular signaling pathway(s) mediated by IL-17RA signaling for preventing and ameliorating AD and to develop new preventive and therapeutic measures (drugs and/or modalities) that target the molecular pathways.